DE1670550B2 - SUBSTITUTED 2-AMINO-4-HYDRAZINO6-PIPERAZINO-S-TRIAZINE - Google Patents

Description

where R ¹ to R ⁵ each represent hydrogen atoms or lower alkyl groups and, in addition, R ^{1 can} also represent a phenyl radical and R ² and R ³ together also represent a benzal radical and R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded, can also form a piperidine, pyrrolidine or morpholine radical, as well as their salts with organic or inorganic acids, show a biological activity and are characterized in particular by their very high anti-inflammatory effectiveness.

The compounds according to the invention can be used in a manner known per se, for. B. produced thereby that one in egg »Trishalogen-s-triazine, preferably Trischlor-s-triazine, introduces the various substituents one after the other. The procedure here is that you first either use a compound of the general formula

Ν — Ν (H)

or with a compound of the general formula

R ⁴

HN

Ϊ \

(III)

R ⁵

where R ¹ to R ⁵ each represent hydrogen atoms or lower alkyl groups and, in addition, R ^{1 can} also represent a phenyl radical and R ² and R ³ together also represent a benzal radical and R ⁴ and R ⁵ together with the nitrogen atom to which they are bonded, can also form a piperidine, pyrrolidine or morpholine radical, as well as their salts with organic or inorganic acids.

implements. The piperazine residue is always introduced last.

Compounds of the general formula

NH-NH ₂

R ⁴ N

N-C

/
R ⁵

N (IV)

Il / -,

C-NH NH

can, for example, also be produced in such a way that one is a compound of the general formula

NH

-N = CH- ^ S

35 R ⁴

Il,
CN

NH

40

45 NC

R ⁵ N

by heating in the presence of an acidic substance or in the presence of excess quantities Treated hydrazine.

The compounds obtained can then be converted into their salts.

When carrying out these processes, for which no protection is claimed here, one can, for example proceed so that one dissolves one reactant in an organic solvent or suspended and the other reactant also dissolved or suspended, optionally in the presence an acid-binding agent, added and the desired reaction temperature through Cooling or heating stops. The substituents to be introduced into the triazine compound should be in at least stoichiometric amounts are used. Depending on the responsiveness of the Partner is advised to reflux for a longer period of time in some cases. in the in general, the starting triazine compound is initially introduced in these reactions and the other Reactants added dropwise to the solution or suspension. At the introduction of the piperazine residue however, it is advisable to proceed in reverse order. It is also possible to use the one Reactants, e.g. B. to introduce the alkylamine in gaseous form.

Acetone, ethyl acetate, methylene chloride and lower alcohols are used as solvents or suspending agents and the like in question.

For the conversion into the salts, the In the manufacture of drugs common acids are used. Examples are sulfur, Phosphorus, hydrogen halide, sulfamine, benzyl sulfone, p-toluenesulfone, maleic, fumaric, amber, Tartaric, lactic, citric, ascorbic, glycolic or salicylic acids.

example 1

a) 53.6 g (0.2 mol) of 2,4-bis-chloro-6-benzalhydrazinos-triazine are suspended in 350 ml of methylene chloride and a solution of 34.8 g with stirring (0.4 MoH morpholine in 50 ml of methylene chloride was added dropwise within 30 minutes, the temperature is kept at 25 ° C. The clear solution becomes morpholine hydrochloride by washing with water removed and the solution concentrated. There are 52.0 g of 2-morpholino-4-chloΓ-6-benzalhydrazino-s-triazine obtained with m.p. 169 to 173 ° C, d. i. 81.6% of theory.

b) 31.9 g (0.1 mol) of the triazine compound obtained are dissolved in a solution of 58.2 g (0.3 mol) of piperazine hexahydrate dissolved in 200 ml of ethyl alcohol and refluxed for 45 minutes. By letting it stand the solution overnight, the dimer formed in small amounts precipitates in crystalline form, which is then filtered off. The filtrate is concentrated and the residue is taken up in methylene chloride and washed with water. After drying and concentrating the solution, it becomes a syrupy residue obtained, which crystallizes on standing. The crystal mass is washed through with about 100 ml of ether, whereby 28 g of 2-morphoIino-4-piperazino-6-benzalhydrazino-s-triazine

NH-N = CH

O H

N H NH

OHN-

-N H NH

Example 2

a) 26.8 g of 2,4-bis-chloro-6-benzalhydrazino-s-triazine (0.1 mol) are suspended in 150 ml of methylene chloride and a solution of at 25 ° C with stirring 16.8 g of piperidine (0.2 mol) in 50 ml of methylene chloride was added dropwise within 30 minutes Solution of precipitated Piperidinhydrocnlorid is through Separated washing with water. After the solution has been dried and concentrated, 23 g of 2-piperidino-4-chloro-6-benzamydra2ino-s-triazine are added obtained with m.p. 122 to 125 ° C, d. L 72.8% of theory

b) 31.7 g (0.1 mol) of the compound obtained in a boiling solution of 58.2 g (03 mol) Piperazine hexahydrate registered in 200 ml of ethyl alcohol, whereby solution takes place. The alcohol is evaporated and the residue was taken up in 200 ml of methylene chloride by washing with water Excess piperazine and piperazine hydrochloride are separated off and the solution is concentrated after drying. 25.6 g of 2-piperidino-4-piperazino-6-benzalhydrazino-s-triazine are obtained

NH-N = CH

having a melting point of 180 to 182 ° C, d. i. 76% the theory.

e) 46.1 g (0.125 mol) of the triazine compound obtained are refluxed for 1 hour together with 31.0 g of hydrazine hydrate in 200 ml of ethyl alcohol. The clear solution obtained is concentrated in vacuo and the residue in 500 ml of methylene chloride and this solution was then washed out 3 times with 25 ml of water each time. After drying the solution is largely concentrated and ether is added until it starts to become cloudy. The 2-morpholino ^ -piperazino-ö-hydrazino-s-triazine

NH-NH ₂
V

This separates out in crystalline form. There are, after filtration, 25.2 g; mp. 150 to 153 receive ^Ü C, di 72% of theory.

N N

<H Ν-Λ J-Π H NH
N

with melting point 192 to 196 ° C, that is 70% of theory.

Example 3

a) 26.8 g (0.1 mol) of ^ bis-chloro-o-benzalhydrazinos-triazine are suspended in 100 ml of methylene chloride and 9.0 g (0.2 mol) of ethylamine in gaseous form Cooling and stirring initiated, the temperature being maintained at 28 ° C. The converted triazine compound is largely insoluble in methylene chloride and becomes pure by filtering and washing with water obtain. Yield: 23.4 g of 2-ethylamino-4-chloro-6-benzalhydrazono-s-triazine; M.p. 180 to 185 C, i.e. i 84.7% of theory.

b) 27.7 g (0.1 mol) of the compound obtained are dissolved in a boiling solution within 30 minutes of 58.2 g (0.3 mol) of piperazine hexahydrate added to 200 ml of ethyl alcohol, with dissolution taking place. To Boiling under reflux for 45 minutes, the solution is left to stand overnight, with by-products retire. After the alcohol has been distilled off, the residue is taken up in methylene chloride and washed with water to separate the excess piperazine and piperazine hydrochloride.

After drying and concentrating the solution, 25.1 g of 2-ethylamino-4-pipeΓazino-6-benzalhydrazinos-triazine

NH-N = CH- / j>

A.
NN

H ₅ C ₂ HN-Ii JN ^ H ^ NH
N

obtained with melting point 104 to 118 ° C. (97%), that is 77% of theory.

Example 4

a) 101.5 g (0.55 mol) of cyanuric chloride are dissolved in 300 ml of ethyl acetate and a solution of 108 g of benzalphenylhydrazo (0.55 mol) and 67 g of collidine (0.55 mol) in 800 ml of ethyl acetate at 50 ° C added dropwise within 2 hours and ^{stirred at 50 0} C for a further 3 hours. After cooling and standing overnight, the suspension formed is filtered off with suction and washed with ethyl acetate and water. After the? Drying gives 145 g of 2,4-bis-chloro-6-phenylbenzalhydrazino-s-triazine with a melting point of 183 to 187 ° C. (97%), that is 76.5% of theory.

b) 129.0 g (0.375 mol) of the triazine compound obtained are suspended in 600 ml of methylene chloride and a solution of 65.2 g (0.75 mol) of Morpho-Ii η in 100 ml of methylene chloride is added dropwise with stirring over the course of 60 minutes, keeping the temperature at 25 ° C. The morpholine hydrochloride is separated off by washing with water. Morpholino - - 4 - chloro - 6 - after concentration of the dried solution 113g 2 are. Phenylbenzalhydrazinos-triazine of melting point 203 to 205 ⁰ C condition, di 76.4% of theory.

c) 39.5 g (0.1 mol) of the compound obtained are in a boiling solution of 58.2 g (0.3 mol) Piperazine hexahydrate registered in 200 ml of ethyl alcohol, whereby solution takes place. After 45 minutes of simmering it is left to stand under reflux overnight to separate out smaller amounts of dimer and then filtered. The solution is concentrated, the residue dissolved in 200 ml of methylene chloride and washed with Washed water, with which the excess of piperazine and the piperazine hydrochloride is separated.

After concentrating the dried solution, 32 g of 2-morpholino-4-pipeΓazino-6-phenyIbenzalhydrazino-s-triazine are obtained

Example 5

36.8 g (0.1 mol) 2-morpholino-4-piperazino-6-benzalhydrazino-s-triazine become one in portions

a boiling solution of 190 g of 36% aqueous HCl (2.0 mol) in 300 ml of ethanol and after Entry heated under Rüdrfluss for 30 minutes. The ethanol is then distilled off, with the split off Benzaldehyde with distilled over. The residue is dissolved in 300 ml of water and clarified by filtration. The solution is brought to pH 10 with 2N NaOH, part of the free hydrazine compound precipitating. The solid is now dissolved in 300 ml of methylene chloride and shakes out the aqueous mother liquor with it. That

Methylene chloride is distilled off and the viscous residue is crystallized with ether. It 23.5 g of 2-morpholino-4-piperazino-6-hydrazino-s-triazine obtained with m.p. 150 to 153 ° C (Z), d. i. 84.1% of theory.

The compound obtained is identical to that prepared according to Example 1c.

The superior effectiveness of the compounds of the present invention is demonstrated by a comparison below shown compounds with phenylbutazone and indomethacin, the obtained Results are given in the following table:

Compound I (example 1b)

Z-Morpholino ^ -piperazino-o-benzalhydrazinos-triazine.

Compound II (example 4c)

2-morpholino-4-pipeΓazino-6-phenyl-benzalhydrazino-s-triazine.

Compound III (example Ic)
2-morpholino-4-piperazino-6-hydrazino-s-triazine.

with a melting point of 180 to 185 ° C., that is 72% of theory.

Compound IV (Example 3b)
2-ethylamino-4-pipeΓazino-6-benzalhydrazinos-triazine.

Compound V (example 2 b)
2- piperidino -4-piperazino-6-benzalhydrazinos-triazine.

link

Phenylbutazone

Indomethacin.
I.

II

III

IV

V

Protein edema

99
82
86

ED Th 180 2.9 350 1 18th 52 6.0 300

Formalin edema

75 0

ED

135

3000

95

28

125

3.9
1

47
79
96
76
76
88
99

Carrag.-Edema Th rat ± LD 50 59 mouse 35 530 23 625 16 approximately 2000 to 4000 about 4000 2000 to 4000 280 ± 288 800 to 1600 1780 ED 16 1.4 1.6 6.0 6.3

% = Udema inhibition in percent at 300 (protein and formalin edema) or at 30 (carrageenin edema) mg / kg orally. ED = ED 50 in mg / kg orally. Th = therapeutic range = LD 50 / ED 50. LD 50 in mg / kg oral.

Claims (1)

Claim: Substituted 2-amino-4-hydrazino-6-piperazino-s-triazines of the general formula I. NH (D It has been found that substituted 2-amino-4-hydrazino-6-piperazino-s-triazines the general formula